Choline kinase is the first enzyme in the Kennedy or phosphatidylcholine (PC) synthesis pathway and phosphorylates choline to phosphorylcholine (PCho) using adenosine 5′-triphosphate (ATP) as a phosphate group donor [Kent, C. Prog. Lipid Res., 29, 87-105 (1990); Kennedy, E. P. Fed. Proc., 20, 934-940 (1961)]. Ras genes form a family called oncogenes, which have been widely studied because they are activated in 25-30% of all human tumors and in some of them in 90% [Bos, J L. Cancer Res 49, 4682-4689 (1989); Kiaris, H., Spandidos, D. A. Int. J. Oncol., 413-421 (1995)]. Ras proteins play an important role in intracellular signal transmission due to their involvement in regulating cell proliferation, terminal differentiation and senescence [Abdellatif, M., MacLellan, W. R.; Schneider, M. D. J. Biol. Chem., 269, 15423-15426 (1994); Wiesmüller, L., Wittinghofer, F. Cell Signal., 6, 247-267 (1994); Barbacid, M. Eur. J. Clin. Invest., 20, 225-235 (1990); Hahn & Weinberg Nat. Rev. Cancer, 2: 331 (2002); Wright & Shay Nat. Biotech, 20: 682 (2002); Drayton & Peters Curr. Op. Gen. Dev, 12:98 (2002)]. The transformation mediated by various oncogenes, amongst which ras oncogenes stand out, induces high levels of choline kinase activity, resulting in an abnormal increase in the intracellular levels of its product, PCho [Lacal et al., Nature 330, 269-272 (1987); Lacal J. C. Mol. Cell. Biol. 10, 333-340 (1990); Teegarden, D., Taparowsky, E. J., Kent, C. J. Biol. Chem. 265, 6042-6047 (1990); Ratnam, S.; Kent, C. Arch. Biochem. Biophys. 323, 313-322 (1995); Ramírez de Molina, A., Rodríguez-González, A., Peñalva, V., Lucas, L., Lacal, J. C. Biochem. Biophys. Res. Commun. 285, 873-879 (2001); Ramírez de Molina, A., Peñalva, V.; Lucas, L., Lacal, J. C. Oncogene 21, 937-946 (2002)]. Supplementary facts support the role of ChoK in the generation of human tumors because studies using nuclear magnetic resonance (NMR) techniques have shown high levels of PCho in human tumor tissues with respect to normal tissues, including, among others, breast, colon, lung and prostate tumors [Ruiz-Cabello, J., Cohen, J. S. NMR Biomed. 5, 226-233 (1992); de Certaines, J. D., Larsen, V. A., Podo, F., Carpinelli, G., Briot, O., Henriksen, O. NMR Biomed. 6, 345-365 (1993); Smith, T. A. D., Bush, C., Jameson, C., Titley, J. C., Leach, M. O., Wilman, D. E. V., McCready, V. R. NMR Biomed. 6, 318-323 (1993)]. It is common knowledge that ras is one of the most profoundly studied oncogenes in human carcinogenesis and that ChoK inhibition has shown to be a new and efficient antitumor strategy in cells transformed by oncogenes [Cuadrado, A., Carnero, A., Dolfi, F., Jiménez, B., Lacal, J. C. Oncogene, 8, 2959-2968 (1993); Jiménez, B., del Peso, L., Montaner, S., Esteve, P. Lacal, J. C. J. Cell Biochem., 57, 141-149 (1995); Hernández-Alcoceba, R., Saniger, L., Campos, J., Núñez, M. C., Khaless, F., Gallo, M. Á., Espinosa, A., Lacal, J. C. Oncogene, 15, 2289-2301 (1997)]. These first observations were later extrapolated in vivo in nude mice [Hernández-Alcoceba, R., Fernández, F., Lacal, J. C. Cancer Res. 59, 3112-3118 (1999)]. The research on ChoK inhibitors has identified Hemicholinium-3 (HC-3) as a relatively powerful and selective blocking agent [Cuadrado A., Carnero A., Dolfi F., Jiménez B. and Lacal J. C. Oncogene 8, 2959-2968 (1993); Jiménez B., del Peso L., Montaner S., Esteve P. and Lacal J. C. J. Cell Biochem. 57, 141-149 (1995); Hernández-Alcoceba, R., Saniger, L., Campos, J., Núñez, M. C., Khaless, F., Gallo, M. Á., Espinosa, A., Lacal, J. C. Oncogene, 15, 2289-2301 (1997)]. This choline homologue with a biphenyl structure has been used to design new antitumor drugs. Since HC-3 is a powerful respiratory paralyzing agent, it is not a good candidate for its clinical use. The synthesis of several derivatives has been based on structural modifications of HC-3 improving the ChoK inhibitory activity and suppressing its toxic effects. The inhibitory effect produced by bisquaternized symmetrical compounds on proliferation has been correlated with the ability to induce PCho production in whole cells [Hernández-Alcoceba, R., Saniger, L., Campos, J., Núñez, M. C., Khaless, F., Gallo, M. Á., Espinosa, A., Lacal, J. C. Oncogene, 15, 2289-2301 (1997) and ES 2 117 950]. When the 1,2-ethylene-p-(bibenzyldimethyl-diyl) residue was used as spacer between the two cationic pyridinium heads substituted in position 4 [Campos, J., Núñez, M. C., Rodríguez, V., Gallo, M. Á., Espinosa, A. Bioorg. & Med. Chem. Lett. 10, 767-770 (2000)], the structures were evaluated by their ability to inhibit the isolated ChoK (in ex vivo conditions) [Lacal J. C. IDrugs 4: 419-426 (2001)]. The 4-NR2 group provided a considerable contribution and it was proposed [Campos, J., Núñez, M. C., Rodríguez, V., Gallo, M. Á., Espinosa, A. Bioorg. & Med. Chem. Lett. 10, 767-770 (2000)] that the role of this group is electronic, by delocalization of the positive charge. The increase in ChoK activity in various human breast carcinomas has been published [Ramírez de Molina, A., Gutiérrez, R., Ramos, M. A., Silva, J. M., Silva, J., Sánchez, J. J., Bonilla, F., Lacal, J. C. Oncogene 21, 4317-4322 (2002)]. It has recently been reported that ChoK alteration is a frequent event in some human tumors such as lung, colorectal and prostate tumors [Ramírez de Molina, A., Rodríguez-González, A., Gutiérrez, R., Martínez-Piñero, L., Sánchez, J. J., Bonilla, F., Rosell, R., Lacal, J. C. Biochem. Biophys. Res. Commun. 296, 580-583 (2002)].
The bisquaternized pyridinium derivatives described in the state of the art and particularly in patent ES 2 117 950, show, however, high levels of toxicity, limiting their extended therapeutic application.
Therefore, in the state of the art there is a need to develop compounds having an activity blocking phosphorylcholine biosynthesis in tumor cells or in processes produced by parasitic, viral, bacterial or fungal infection, and, at the same time, having low levels of toxicity.
The authors of the present invention have discovered, after diligent research, that certain modifications in the structure of the compounds described in the state of the art and particularly in patent ES 2 117 950, have an unexpectedly and therefore surprisingly significant decrease in the levels of toxicity of said compounds of the state of the art.